Tracking changes in average glycemia in diabetics

ABSTRACT

A method, system and computer readable medium for tracking changes in average glycemia in diabetes is based on a conceptually new approach to the retrieval of SMBG data. Using the understanding of HbA 1 c fluctuation as the measurable effect of the action of an underlying dynamical system, SMBG provides occasional glimpses at the state of this system and, using these measurements, the hidden underlying system trajectory can be reconstructed for individual diabetes patients. Using compartmental modeling a new two-step algorithm is provided that includes: (i) real-time estimate of HbA 1 c from fasting glucose readings, updated with any new incoming fasting SMBG data point(s), and (ii) initialization and calibration of the estimated HbA 1 c trace with daily SMBG profiles obtained periodically. The estimation of these profiles includes a factorial model capturing daily BG variability within two latent factors.

CROSS-REFERENCE TO RELATED APPLICATIONS AND CLAIM OF PRIORITY

This application claims priority under 35 U.S.C. § 119(e) and PCTArticle 8 and Rule 4.10, from copending U.S. Provisional ApplicationSer. No. 61/767,451 filed on 21 Feb. 2013, which application isincorporated herein by reference in its entirety.

BACKGROUND OF THE INVENTION

Since the discovery of an “unusual hemoglobin in patients withdiabetes,” over 40 years ago¹, Hemoglobin A1c (HbA1c) has become theestablished standard clinical measurement used as a marker for glycemiccontrol. HbA1c is formed when hemoglobin joins with glucose in theblood, resulting in a glycosylated hemoglobin molecule. Due to the factthat red blood cells survive for 8-12 weeks before renewal, a patient'sHbA1c reflects the average blood glucose levels over the past 3 months.

The widespread acceptance of this measurement has primarily been drivenby two pivotal, large-scale studies in Type 1 (Diabetes Control andComplications Trial; DCCT) and Type 2 (UK Prospective Diabetes Study;UKPDS) diabetes. These prospective, randomized, controlled trials ofintensive versus standard glycemic control in patients with relativelyrecently diagnosed diabetes demonstrated that intensive glucose control,as measured by blood glucose and HbA1c, correlated with a decreased riskof diabetes-related complications^(2,3). The DCCT and UKPDS, along withother clinical studies, also have been used to support the developmentof hypothetical scenarios and test mathematical calculation models whichaim to describe the relationship between HbA1c and blood glucose.

Linear Models for Blood Glucose-HbA1c Relationship

Based on the UKPDS in type 2 diabetes (T2D) patients a linear regressionrelationship of HbA1c with fasting plasma glucose (FPG) was observed,where FPG=1.28 (HbA1c)−0.66 (r2=0.59).⁴ Similarly, using data from theDCCT in type 1 diabetes (T1D) patients, Rohlfing et al. analyzed 26,056values based on 7 mean blood glucose (MPG) measures per day.⁵ Using thisapproach, they established a linear relationship between plasma glucoseand HbA1c (MPG (mmol/l)=(1.98×HbA1c)−4.29 or MPG(mg/dl)=(35.6×HbA1c)−77.3; r=0.82). This was subsequently used for theAmerican Diabetes Association (ADA) Standards of Medical Care inDiabetes to describe the correlation between HbA1c and mean glucose.However, in the most recent update, it is now considered that this wasnot optimal, being derived from relatively sparse data (one 7-pointprofile over 1 day per HbA1c reading) in the primarily Caucasian T1Dparticipants of the DCCT.⁶

More recently, the ADAG Study Group evaluated data from T1D, T2D andNon-Diabetic patients using self-monitored blood glucose (SMBG).⁷ Theaim was to define a relationship between HbA1c and average glucose (AG)levels and determine whether HbA1c could be expressed and reported as AGin the same units as used in self-monitoring. Approximately 2,700glucose values were obtained for each subject during 3 months. Linearregression between the HbA1c and AG values provided the closestcorrelations, allowing for calculation of an estimated average glucose(eAG) for HbA1c values using the formula AG (mg/dl)=28.7*A1c−46.7;r2=0.84; P<0.0001. Furthermore the authors found that the linearregression equations did not differ significantly across sub-groupsbased on age, sex, diabetes type, race/ethnicity, or smoking status.This has now been adopted as the current recommended relationship to useaccording to the ADA 2011 Standards of Medical Care in Diabetes.⁶

Makris, et al have also observed a similar data pattern, with a strongcorrelation seen between MBG and HbA1c in Type 2 diabetic patients,using the formula MBG (mg/dl)=(34.74*HbA1c)−79.21 or MBG(mmol/l)=1.91*HbA1c−4.36; r=0.93. They also found that the linearregression of MBG values vs. HbA1c at 12 weeks was statisticallysignificant; whereas other independent variables of sex, age, body massindex (BMI) and patient status (Type 2 diabetes treated or not) werenot.⁸ Temsch et al also identified issues with a linear mathematicalmodel developed to calculate HbA1c values based on SMBG and past HbA1clevels (HbA1c=2.6+0.03*G [mg/100 ml] or 2.6+0.54*G [mmol/l]). Overall,the predicted HbA1c values were consistent with measured values andresults matched the HbA1c formula in the elevated range. However, themodel was found to be too optimistic in the range of better glycemiccontrol. Sub-analysis suggested that bias may have been introduced byuse of different glucometers and individual measurement habits.⁹

Factors Influencing the Relationship between Blood Glucose and HbA1c

A range of factors have been postulated to influence the relationshipHbA1c and blood glucose, such as patient's age, body weight (BMI),gender, ethnicity, behavioral characteristics (e.g. time and frequencyof blood glucose measurement) and their general status such as durationand type of diabetes, concomitant diseases, etc.^(10,11,12,13). Inparticular, two critical areas have been identified which appear to havesignificant impact on this relationship:

-   -   1) The time of blood glucose measurement (fasting (FPG),        post-prandial etc.) and    -   2) The frequency and timing of blood glucose measurement.

Whilst postprandial hyperglycemia, like preprandial hyperglycemia,contributes to elevated HbA1c levels, its relative contribution ishigher at HbA1c levels that are closer to 7%. However, the major outcomestudies such as the DCCT and UKPDS, relied overwhelmingly onpre-prandial SMBG. Analysis of DCCT found that among individual timepoints, the afternoon and evening prandial glucose (post-lunch,pre-dinner, post-dinner, and bedtime) readings showed highercorrelations with HbA1c than the morning time points (pre-breakfast,post-breakfast, and pre-lunch), with the best correlation of HbA1c beingthe area under the glucose profile.¹⁴ Yamamoto-Honda et al also showedthat FPG and 2-h post-breakfast blood glucose (PBBG) levels exhibited agood sensitivity and specificity for predicting a glycemic control,while the FPG and 3-h PBBG levels only exhibited fair sensitivity andspecificity for predicting glycemic control.¹⁵ Similarly chronology andfrequency of blood glucose measurements also has influence on therelationship between blood glucose and HbA1c. At any given time, a givenblood sample contains erythrocytes of varying ages, with differentlevels of exposure to hyperglycemia. Whilst the older erythrocytes arelikely to have more exposure to hyperglycemia, younger erythrocytes aremore numerous. Blood glucose levels from the preceding 30 dayscontribute approximately 50% to HbA1c, whereas those from the period90-120 days earlier contribute only approximately 10%.¹⁶ Exploitingfurther the timing of blood glucose measurements, Trevino challenged thelinear model approach as fundamentally flawed and had instead pursuedweighted average and nonlinear approaches.^(17,18,19)

Development of Non-Linear Models for Blood Glucose-HbA1c Relationship

Several nonlinear models have been proposed, which aim to addressadditional key factors that influence the relationship between bloodglucose and HbA1c. Zielke et al proposed that HbA1c values reflect serumglucose levels of the immediate past much better than levels severalweeks ago. Using a biomathematical model that takes into account thechemical reactions during HbA1c formation as well as the life cycle ofhuman erythrocytes, they concluded that in order to ensure some degreeof reliability of HbA1c measurements, these readings should not bespaced too far apart.²⁰ Ollerton et al developed an approach to addressthe relative contribution of fasting and post-prandial glucose levels tothe value of HbA1c, using a mathematical model of hemoglobin glycation.They highlighted that this is based on physiologically reasonableassumptions, to derive a compartmental differential equation model forHbA1c dynamics.²¹ Other groups have used data from clinical studies(including DCCT) and hypothetical scenarios, to propose models whichincorporate the kinetics of HbA1c formation and removal, in order tobetter describe the relationship between HbA1c and BGC.^(22,23) However,while many of these models may possibly be theoretically sound to someextent, none so far have offered a practically-applicable dynamicalapproach to tracing the fluctuations of HbA1c over time, an approachthat could result in application deployed in an SMBG device ensuringsufficient accuracy by sparse (e.g. fasting glucoses and occasional 7points profiles) BG measurements.

Risk Analysis of Blood Glucose Data

The present inventors' group at the University of Virginia has alsoworked extensively on developing models of the relationship between SMBGand HbA1c. In an early study in T1D patients, we investigated how wellthe mean of SMBG data describes the actual mean BG.²⁴ The linear formulaHbA1c=5.21+0.39*BGMM (mean SMBG expressed in mmol/liter) resulted in acorrelation of 0.7 between mean SMBG and HbA1c. Later, an updated linearrelationship was derived: HbA1c=0.41046*BGMM+4.0775. However, due to anumber of factors associated with routine SMBG, only about 50% of thevariance of the actual BG was accounted for by mean SMBG. Thus, thesefindings suggested that mean SMBG was far from an ideal descriptor ofactual average glycemia.

To correct for imperfections in SMBG sampling, we have introducednonlinear corrections for the SMBG-based estimates of HbA1c, which usedresults from our theory of risk analysis of BG data²⁵, namely the Lowand High BG Indices (LBGI and HBGI). These nonlinear correctionsresulted in improved numerical estimation of HbA1c from SMBG data andintroduced mean absolute deviation (MAD) and mean absolute relativedeviation (MARD) as measures of the accuracy of HbA1c estimation.²⁶ Thissimple step was important for the understanding of HbA1c estimationbecause while correlation alone measures the strength of a linearassociation, it does not measure any possible offset of the estimates.For example, an estimate having two-fold higher values than actual HbA1cwould have perfect correlation with HbA1c.

Further, based on our risk analysis theory, we introduced a method,system, and computer program, which was designed to aid the control inboth T1 and T2 diabetic patients, by predicting from SMBG readings thelong-term exposure to hyperglycemia, as well as the long-term andshort-term risks for severe or moderate hypoglycemia.²⁷ This approachused the HBGI and the LBGI, and later a new algorithm which derived anaverage daily risk range (ADRR)—a variability measure computed fromroutine SMBG data. We found that the ADRR provided a superior balance ofsensitivity for predicting both hypoglycemia and hyperglycemia.²⁸

Most importantly for this presentation, we have conducted the largest todate study of the effects of offering real-time SMBG-based estimation ofHBA1c, LBGI, and ADRR to patients with diabetes in their naturalenvironment. In this study, 120 people with T1D used for 8-9 months ameter and a handheld computer providing these glycemic markers at eachSMBG entry. As a result, average glycemic control was significantlyimproved, the incidence of severe hypoglycemia was reduced, and thepatients rated highly the utility of the provided feedback.²⁹

SUMMARY OF THE INVENTION

The above study offered empirical evidence supporting the long-standingbelief that providing real-time estimates of HbA1c and risk forhypoglycemia has the desired effect of improving glycemic control.Taking this message forward, we now propose a novel and non-obviousmodel-based approach (method, system and computer readable medium) to,among other things, track changes in average glycemia from SMBG data.Unlike previously introduced models, this technique (method, system, andcomputer readable medium) allows for:

-   -   Simple parameterization of the dynamics of average glycemia and        thereby HbA1c, with two parameters that can be individually        tuned to the physiology an behavior of each person;    -   Robust estimation procedure capable of working on sparse        readings of fasting BG and occasional (e.g. monthly) 7-point        SMBG profiles; and    -   Inherent capability for calibration of the algorithm (e.g.,        method) using SMBG profiles.

An aspect of an embodiment of the present invention provides a method,system and computer readable medium for tracking changes in averageglycemia in diabetes, based on a conceptually new approach (method andtechnique) to the retrieval of SMBG data. A principal premise of thisapproach is, among other things, the understanding of HbA1c fluctuationas the measurable effect of the action of an underlying dynamicalsystem. SMBG provides occasional glimpses at the state of this systemand, using these measurements, the hidden underlying system trajectorycan be reconstructed for each individual.

Using compartmental modeling—a technique well established in diabetesresearch³⁵—we have constructed a new two-step algorithm (and relatedmethod, system and computer readable medium) that includes: (i)real-time estimate of HbA1c from fasting glucose readings, updated withany new incoming fasting SMBG data point, and (ii) initialization andcalibration of the estimated HbA1c trace with daily SMBG profiles takenapproximately every month. The estimation of these 7-point profilesincludes another innovative step—a factorial model capturing daily BGvariability into two latent factors.

BRIEF DESCRIPTION OF THE DRAWINGS

The new method, system and computer-readable medium will become moreunderstood from the following detail description, together with detailedalgorithm (e.g., technique) and data requirements for its implementationin a portable SMBG device or other desired or required systems ordevices, in conjunction with the accompanying drawings, wherein:

FIG. 1 is a schematic diagram of a system architecture of an HbA1cestimation procedure in accordance with the invention;

FIG. 2 is a diagram showing a one-compartment model of hemoglobinglycation in accordance with the invention;

FIG. 3 is a graph of a Dynamical HbA1c Tracking Procedure in accordancewith the invention;

FIG. 4 is a diagram of an HbA1c error-grid for a dynamical HbA1ctracking procedure in accordance with the invention;

FIG. 5 is a diagram of an HbA1c error-grid for a linear estimate ofHbA1c in accordance with the invention;

FIG. 6 is a graphical analysis of A1c rate of change in accordance withthe invention, wherein the wider bars represent lab values, and thenarrow bars represent estimates;

FIG. 7 is a graph showing the effect of missing fasting BG on eA1cestimator performances sensitivity to erroneous profiles in accordancewith the invention;

FIG. 8 is a graph showing the effect of scrambled profile tags on eA1cestimator performances sensitivity to alternate site testing (AST) inaccordance with the invention;

FIG. 9 is a high level functional block diagram of an embodiment of thepresent invention, or an aspect of an embodiment of the presentinvention;

FIG. 10A is a block diagram of a computing device usable with theinvention;

FIG. 10B is a diagram of a network system in which embodiments of theinvention can be implemented;

FIG. 11 is a block diagram of a computer system with Internetconnectivity, in which an embodiment of the invention may beimplemented; and

FIG. 12 is a diagram of a system embodiment in accordance with theinvention.

DETAILED DESCRIPTION OF THE INVENTION Algorithm Concept: DynamicalTracking of Changes In Average Glycemia

Conceptually, a non-limiting embodiment of the estimation procedure forthe present invention method, system, and computer readable mediumproposed in this disclosure works as follows:

-   -   Fasting SMBG readings are submitted to a model of HbA1c        dynamics, which tracks the fluctuations of average glycemia over        time. This model depends on two individually-adjustable        parameters, one of which is fixed to a population value as        described below, and the other of which is used to provide        inherent ability to individualize (calibrate) the dynamics of        HbA1c to a particular person at a particular point in time. For        simplification of explanation only, in the exemplary        implementation the calibration is fixed for all users.    -   Periodically (e.g. once a month) a daily SMBG profile is        submitted to a factorial model, which reconstructs a person's        daily glucose variability via two principal factors (components)        that are linear combinations with fixed coefficients of the SMBG        values recorded during the day. In this implementation we use        standard 7-point profiles;    -   The factors are then used to calibrate the model for        peri-prandial (i.e. pre-prandial and post-prandial) BG        deviations from fasting. In other words, the amplitude        (variability) of glucose fluctuation is captured using the        7-point profile and is used to adjust the dynamical model to        better reflect average glycemia.    -   Finally an infrequent (1-3 times a year) reference HbA1c        measurement can be used to calibrate the glycation formula (link        between HbA1c and glucose exposure).

FIG. 1 shows a system for the estimation procedure flow. In essence,SMBG measurements are divided in two groups, (i) fasting glucosemeasurements (1) and (ii) profile glucose measurements (2). Fastingglucose readings are expected once in a couple of days and are the maindriving function of the model, while profile measurements are scarce(e.g. monthly) and allow for calibration of the glucose exposurefunction to the patient's glucose variability. The final result is anestimate of Hba1c (4) that is updated with any incoming fasting SMBGdata point (1) and is calibrated with any incoming 7-point profile (2).The SMBG-only system can function as such or be enhanced by referenceHbA1c (3) calibration of the calibration formula; in the absence ofHbA1c reference (3), the system uses a fixed glycation formula.

Datasets:

The data for training and test data set were provided bySanofi-Deutschland GmbH originating from the phase IIIb study: TargetGlycemic Control and the Incidence of Symptomatic Nocturnal Hypoglycemiain Insulin Naïve Subjects with Type 2 Diabetes on Oral HypoglycemicAgent(s) and Treated with Insulin Glargine or NPH Human Insulin, HOE901,4002.

This study was conducted in Type 2 DM patients between 7 Jan. 2000 and22 Oct. 2001 in 80 study centers in USA and Canada.

The demographics of the ITT study population can be found in Table 1.

Training data set: All formulas were developed using a training data setprovided by Sanofi-Aventis Deutschland GmbH, which contained 17,863fasting SMBG readings and approximately monthly 7-point profiles for 379individuals with type 2 diabetes (see Table 1 for details.)

On average, each individual contributed 47 days of data. After using thetraining data, all formulas were fixed and then applied withoutmodification to a test and to an external-validation dataset.

Test data set provided by Sanofi-Aventis Deutschland GmbH was used tovalidate the formulas developed on the training data. The test data setcontained 17,925 fasting SMBG readings and approximately monthly 7-pointprofiles for 375 individuals with type2 diabetes (see Table 1 fordetails). On average, each individual contributed 48 days of data.

TABLE 1 Demographics/summary table for training and testing data setsFemale Men Age Average 54 years 56 years Age Standard deviation 9.2 9.2Age Min 29 years 30 years Age Max 74 years 75 years BMI Average 33.4kg/m2 31.5 kg/m2 Duration Diabetes 8.6 years 8.7 years Height Average162.9 cm 177.3 cm Race White: 263 White: 369 Black: 59 Black: 34 Multi:3 Multi: 6 Asian: 10 Asian: 12 Sex (754 participants) 44.31% 55.69%Weight Average 88.9 kg 99.5 kg Pregnancy test (712 participants) Notapplicable: 657 Negative: 47 Error Entry: 8 HbA1c (4351 datapoints) SD:1.1 Avg: 7.6% Min: 5.2% Max: 12.2%

Variables:

The variable names were unified across the data sets and are as follows:

-   -   SUBNO—subject ID number;    -   PGDT—time (day) of glucose measurement;    -   PG1—fasting BG measured pre-breakfast every day;    -   PG2 to PG8—BG measurements forming a 7-point profile:        -   PG2: first meal preprandial        -   PG3: first meal postprandial        -   PG4: second meal preprandial        -   PG5: second meal postprandial        -   PG6: third meal preprandial        -   PG7: third meal postprandial        -   PG8: before bedtime

Modeling of Fasting BG: Dynamics of HBA1c

First, a dynamic model of hemoglobin glycation and clearance isconstructed, as shown in FIG. 2. Being mindful that the final goal ofthe resulting algorithm (method and related system) may be deployment ina portable device with limited computing power, we limit this model to aone-compartment representation.

This model corresponds to a first order differential equation:

∂ t = - 1 τ  ( - f  ( SMBG t ) ( 1 )

where the function f(SMBG_(t)) is a function using self-monitoring datato track glycemia exposure over time.

Modeling 7-Point Profiles: Factorial Model of Daily Glucose Variability

Using the training data, a linear model is constructed of the primaryfactors determining a 7-point profile of SMBG. The reason that we haveopted for factors (or principal components) of this profile instead ofindividual data are the following:

-   -   Statistically, latent factors tend to be more stable and        reproducible across diverse data sets;    -   Collapsing the entire profile into two factors allows for easy        handling of missing data: a missing value in a 7-point profile        can be simply imputed in the factorial representation.        With this understanding, the factors are computed as follows:

θ₁=0.4006*PG2+0.4645*PG3+0.3753*PG4+0.2411*PG5−0.1805*PG6−0.2528*PG7+0.0481*PG8  (2)

θ₂=−0.1557*PG2−0.2077*PG−0.1177*PG+0.0341*PG5+0.5255*PG6+0.6014*PG7+0.2543*PG8  (3)

Computational Algorithm:

The implementation of the dynamical model and of factorial models ofHbA1c includes initial estimation of Hba1c, tracking of HbA1cfluctuations over time, and occasional (e.g. monthly) calibrations ofthe tracking value. The initial and the calibration values of HbA1c areobtained using the same formula. The tracking procedure uses thedynamical model of HbA1c setting its parameter values at γ=0.99 andτ=20. These two parameters are kept fixed throughout the estimationprocedure. The end result is an estimated value of HbA1c, eA1c, given bythe formulas below:

Step 1 (optional)—Calibration of HbA1c is derived from the factorialmodel of 7-point profiles presented in the previous section. Calibrationvalues for HbA1c are computed using the formula:

$\begin{matrix}{{{CalA}\; 1c} = {{\frac{6.507}{1000}*\theta_{1}} + {\frac{4.353}{1000}*\theta_{2}}}} & (4)\end{matrix}$

Where: CalA1c is the calibration value for HbA1c derived from the mostrecent profile;

θ₁ and θ₂ are the factors defined in the Factorial Model presentedabove. In the absence of a profile to calibrate, θ1 and θ2 are fixed(e.g. 180).

Step 2—Initial Estimate, and Tracking Changes in Average Glycemia:

The glycation function is given by the formula:

$\begin{matrix}{{f( {SMBG}_{t} )} = {{MAX}( {{\gamma*( {4.7561 + {\frac{4.854}{1000}*{{mP}_{0}(t)}} + {{CalA}\; 1c}} )},5} )}} & (5)\end{matrix}$

Where:

-   -   mP₀(t) is the average fasting glucose over the past 5 days and        is updated every time a new fasting glucose is measured,    -   CalA1c is the calibration offset as computed at the previous        step.    -   γ is the glycation efficacy parameter and is fixed by default at        0.99 (unless modified by step 3)

Initial Estimate:

To compute an initial estimate (when the device is first used or if are-initialization is required (see Data Requirements section below) thetracking function is used directly:

eA1c(t ₀)=f(SMBG _(t) ₀ )   (6)

Runtime Estimate

The HbA1c estimate is updated using the dynamic model presented in FIG.2. For example, the glycation function can be fed into a discretizedversion (1 day time step) of the dynamic equation above to produce theupdated HbA1c estimate eA1c(t): at any time t after initialization ofthe algorithm:

eA1c(t)=0.95*eA1c(t−1 day)+0.05*f(SMBG _(t))   (7)

In addition, the output of the eA1c algorithm is saturated: instead ofproviding numerical estimates, values below 6% or above 10% are reportedas Low and High respectively. This is done for the following threereasons:

-   -   (i) First, clinically, values below 6% are equivalent to values        observed in non-diabetics and do not require any action, while        values above 10 require significant clinical action regardless        of the exact number;    -   (ii) Second, any estimation procedure would be less robust at        the extremes of the HbA1c range and therefore including extreme        values would lower unnecessarily its accuracy. This is valid for        any estimation, not for this method alone;    -   (iii) Third, in these data sets, values below 6% and above 10%        include less than 5% of all HbA1c records (2.8% below 6 and 1.4%        above 10); thus, focusing on the clinically-relevant range of        6-10% HbA1c is also statistically justified.

Step 3 (optional)—Glvcation Formula Calibration:

Equation (5) can be modified using a reference HbA1c calibration:

γ is set in equation (5) so that the eA1c value corresponding to thereference HbA1c measurement. This calibration can occur at anytime inthe functioning of the algorithm (e.g., method and related system) butis most efficient after at least a month of data collection.

RESULTS

An Example: (Patient 291039): FIG. 3 illustrates the procedure trackingchanges in average glycemia during normal operation of the method usingfasting glucose and 7-point profiles assessed approximately once a month(Fasting and Profiles); with no 7-point profile available (Fasting dataonly); and enhanced by a 1 point reference HbA1c calibration (Fastingand Profiles with 1 Point Calibration).

Accuracy of the Model-Based eA1c Compared to Model-Free Linear Formula:

In the tables below, the accuracy of estimation of HbA1c (eA1c) usingthe dynamical method detailed above omitting step 3 (first line of thetable) is presented. For comparison with prior established methods, thesecond line of the table includes the same results for the widelyaccepted Nathan's linear formula' applied on the last 2 weeks of data.In addition to correlations, we use Mean Absolute Deviation (MAD) andMean Absolute Relative Deviation (MARD) as standard approaches toaccuracy evaluation:

TABLE 2 Training data: in the training data set, the method produced thefollowing results: Correlation with Type of Algorithm Operationreference HbA1c MAD MARD eAlc - Dynamic HbA1c Tracking 0.85 0.39 5.2%(steps 1-3): tracking fasting glucose; calibration with 7-point profilesapproximately once a month and one reference HbAl c eAlc - Dynamic HbA1cTracking 0.76 0.48 6.6% (steps 1-2): tracking fasting glucose;calibration with 7-point profiles approximately once a month Establishedlinear formula 0.73 0.96 12.8% (Nathan et al⁷)

While the table above presents a comparison of our dynamical HbA1ctracking procedure in the training data initially used for algorithmdevelopment, the table below presents the same comparisons in a data setthat was not used for algorithm development. Thus, Table 3 below shouldbe viewed as the “true test” of algorithm performance as compared towell-established contemporary methods:

TABLE 3 Test data: in the test data set, the method produced thefollowing results: Correlation with Mode of Algorithm Operationreference HbA1c MAD MARD eAlc - Dynamic HbA1c Tracking 0.87 0.40 5.3%(steps 1-3): tracking fasting glucose; calibration with 7-point profilesapproximately once a month and one reference HbAl c eAlc - Dynamic AleTracking 0.76 0.51 6.8% (steps 1-2):: tracking fasting glucose;calibration with 7-point profiles approximately once a month Establishedlinear formula 0.73 0.98 13.1% (Nathan et al⁷)

It is considered that the most important result above may be MARD—themetric that is typically used to assess accuracy of any directmeasurement or other assessment of unknown analyte. Achieving MARD wellbelow 10% signifies that the method is capable of providing accurate andprecise tracking of changes in average glycemia over time.

These results indicate that the dynamical estimation procedure proposedherein produces substantially more accurate estimates of HbA1c than thelatest widely accepted linear methods. Better accuracy is evident in alldata sets used for the testing of the procedure.

Using the dynamical eA1c over other established procedures isparticularly adapted to sparse data, e.g. where only fasting glucose isavailable together with occasional 7-point profiles and simple averagesare likely to be biased. In this particular situation (which is commonin Type 2 diabetes), having an underlying model has clear robustnessadvantages over a model-free linear procedure, which is heavilyinfluenced by missing data and tends to produce biased results whenlimited data is available.

Distribution of eA1c Errors and Trends

This section focuses only on the SMBG-only based A1c estimation (steps1-2)

HbA1c Error-Grid Analysis

Looking at the distribution of estimation error in the test data set(Table 2), we can make the following statements:

-   -   more than 95% of eA1c values fall within ±17% of a standard lab        reference measurement; corresponding to 95% of the eA1c values        within ±1.17 HbA1c units (%) of the laboratory value.    -   more than 61% of eA1c values fall within ±7% of a standard lab        reference measurement; corresponding to 61% of the eA1c values        within ±0.52 HbA1c units (%) of the laboratory value.    -   more than 53% eA1c values fall within ±6% of a standard lab        reference measurement.; corresponding to 53% of the eA1c values        within ±0.44 HbA1c units (%) of the laboratory value.

A detailed look at the accuracy of HbA1c estimation is presented in thefollowing pages, beginning with an error-grid type presentation of eA1cvalues vs. reference HbA1c. The Hba1c error-grid plot below is inspiredby graphical error analyses presented in the past for the assessment ofthe accuracy of SMBG devices, e.g. Clarke Error-Grid³⁰ or Parkes (alsoknown as Consensus) Error−. Constructing the HbA1c Error Grid we haverelied in our extensive expertise Grid³¹ analyses with this type ofanalyses which includes, but is not limited to, the introduction of theContinuous Error Grid now used for evaluation of the accuracy ofcontinuous glucose monitors³² and recommended by the Clinical andLaboratory Standardization Institute (CLSI) for this purpose³³.

Following the tradition of these Error-Grid plots, we define A-zone foreA1c accuracy as follows:

-   -   eA1c is within 10% from reference HbA1c value, or    -   Both reference HbA1c and eA1c are below 6% Hba1c, or    -   Both reference HbA1c and eA1c are above 10% Hba1c.

B-zone is defined as eA1c that is within 20% from reference HbA1c value(note that in the established Clarke and Parkes error-grids, the A-zoneis 20%; thus our analysis is substantially more demanding). Typically,A-zone is referred to as “Accurate” while B-Zone is referred to as“Benign errors” ^(30,31) which are generally acceptable in theevaluation of SMBG devices i.e. the cumulative percentage of A+B zonedata pairs is used as a metric of device accuracy. Pairs outside of theA+B zones are generally considered erroneous.

HbA1c Error-Grid Analysis for eA1c in the Test Data Set

With the above in mind, FIG. 4 presents the HbA1c Error-Grid plot foreA1c computed by the formulas above in the Test data set provided bySanofi-Aventis (Table 2). The data is stratified by reference HbA1cvalues below 6% (green or hollow circles at the left-hand side of thegrid), 6-10% (solid or blue circles) and above 10% (red or hollowcircles at the right-hand side of the grid).

In FIG. 4, 76.2% of the all data pairs fall within Zone A of the gridand 97.5% fall within Zones A+B of the grid. If limited to thereportable HbA1c range (6-10%), the accuracy increases to 78.3% A-zoneand 98.6% A+B zone, which is comparable to the accuracy of SMBG devicesused for BG measurement in the clinical practice. Thus, the estimate ofHbA1c derived from SMBG is comparable to the accuracy of the originalSMBG readings³⁴. This means that the model-based estimation proceduredoes not introduce further bias in the estimate, beyond the errorsinherent with the input SMBG data.

HbA1c Error-Grid Analysis for the Linear Formula in the Test Data Set

Further, to compare the performance of the model-based eA1c tomodel-free linear estimators of HbA1c we use the same Test data set andplot the HbA1c Error-Grid for the established linear model introduced byNathan et al⁷.

The grid in FIG. 5 shows that the linear formula tends to overestimatesignificantly HbA1c, particularly readings above 8% HbA1c, and tounderestimate HbA1c readings below 6%. This results in only 43.8% of theall data pairs within.

Zone A of the grid and only 78.6% within Zones A+B of the grid (slightlylower—42.5% and 78%—if the analysis is limited to reference HbA1c of6-10%). Thus, the linear model has higher error estimating HbA1c thanthe SMBG data it uses as input. It follows that in this case the linearmodel tends to amplify the SMBG errors of its input.

The 20-percent difference in A+B zone hits observed between themodel-based eA1c and Nathan's linear formula is not only verysubstantial, but also highlights a basic requirement for any estimationprocedure: besides the errors inherent in the data, a good estimatorshould not introduce additional errors due to the estimation procedureitself.

Distribution of HbA1c Rate of Change

Looking at the distributions of the HbA1c daily rate of change observedin reference HbA1c values and in the dynamical estimate eA1c, we seethat these two distributions are very similar (FIG. 6, wide bars forlaboratory values). The data shows that there is no difference in therate of change distributions in laboratory and estimated HbA1c. Thus,accurate trend arrows can be displayed using eA1. The proposed trendingsystem displays down/flat/up arrows, based on the absolute change ineA1c, conditions for arrow display is as follows:

-   arrow up: eA1c is increasing faster than 0.01% per day    (corresponding to an approximately 0.3% eA1c increase in a month);-   arrow down: eA1c is decreasing faster than 0.01% per day    (corresponding to an approximately 0.3% eA1c decrease in a month);-   arrow flat: absolute eA1c changes are less or equal to 0.01% per    day.

FIG. 6 is a bar chart showing analysis of the A1c rate of change (widerbars: lab values; narrow bars: estimate).

Robustness Analysis Stratification of the Estimation Error by ReferenceHbA1c Levels

By breaking down the accuracy of the HbA1c estimate by HbA1c values, wecan determine how precise the eA1c estimate is given a laboratory HbA1cvalue. We stratify the testing data set by reference HbA1c and observethat the estimation procedure is most accurate in the 7% to 8% rangewith no bias and 4.5% MARD, which compares favorably to the Nathan'sformula⁷ (−0.81% bias and MARD 14.4%). Perfoiniance degrades on bothside of the optimal range. It is to be noted that the eA1c algorithm isdesigned to not report values below 6% and above 10% (Lo and Hidisplays). Within the HbA1c range of 6-10% the bias of eA1c is alwaysless than 1% HbA1c and MARD is below 10%. Complete results are providedin the tables below:

TABLE 4 Bias stratified by laboratory HbA1c levels HbA1c < 6 6 ≤ HbA1c <7 7 ≤ HbA1c < 8 8 ≤ HbA1c < 9 9 ≤ HbA1c ≤ 10 HbA1c > 10 eA1c 1.02  0.49−0.03 −0.37 −0.83 −1.46 algorithm n = 40 n = 516 n = 608 n = 265 n = 113n = 19 Nathan's 0.09 −0.53 −0.81 −0.26 0.3  0.53 formula n = 43 n = 518n = 616 n = 268 n = 115 n = 23 Reportable HbA1c Range

TABLE 5 MARD stratified by laboratory HbA1c levels HbA1c < 6 6 ≤ HbA1c <7 7 ≤ HbA1c < 8 8 ≤ HbA1c < 9 9 ≤ HbA1c ≤ 10 HbA1c > 10 eA1c 17.89  8.01 4.48  6.51  9.49 14.16 algorithm n = 40 n = 516 n = 608 n = 265 n = 113n = 19 Nathan's 10.81 11.19 14.44 14.19 12.32 15.06 formula n = 43 n =518 n = 616 n = 268 n = 115 n = 23 Reportable HbA1c Range

Stratification of the Estimation Error by Estimated HbA1c Levels

To answer the question “how much trust should one have, given an eA1creading?” we offer another type of analysis: stratification of accuracyalong estimated, not the reference HbA1c. First note that eA1c shouldnot be used to report any values below 6% or above 10% by design. Withinthese confines, the eA1c algorithm is very stable, resulting in HbA1cbiases between −0.23% and 0.19% and MARDs between 6.74% and 7.24%. Incontrast, Nathan's formula shows a clear negative bias at low values andpositive bias at high values, likely resulting from heavier weighting offasting BG in the calculation of the mean. MARD for the Nathan's formulais always higher than for eA1c, with large values (18.3% and 22.5%) atthe extremes. In addition, note that the Nathan's formula often predictslow HbA1c (<6%): 527 data points, compared to only 43 true HbA1c valuesbelow 6%. Complete results are presented below; see also FIG. 4 and FIG.5:

TABLE 6 Bias and MARD for eA1c stratified by eA1c levels eA1c < 6 6 ≤eA1c < 7 7 ≤ eA1c < 8 8 ≤ eA1c < 9 9 ≤ eA1c ≤ 10 eA1c > 10 eA1c NA 0.110.07 −0.23 0.19 NA algorithm n = 0 n = 397 n = 870 n = 243 n = 51 n = 7NA 6.74 6.80 6.9 7.24 NA n = 0 n = 397 n = 870 n = 243 n = 51 n = 7Reportable eA1c Range

TABLE 7 Bias and MARD for Nathan's formula stratified by the levels ofNathan's formula estimate < 6 6 ≤ est. < 7 7 ≤ est. < 8 8 ≤ est. < 9 9 ≤est. ≤ 10 est. > 10 Nathan's −1.29 −0.69 −0.23  0.19  0.73  2.00 formulan = 527 n = 497 n = 237 n = 134 n = 95 n = 92 18.34 10.27 7.68 7.5610.95 22.51 n = 527 n = 497 n = 237 n = 135 n = 95 n = 92 ReportableeA1c Range

Analysis of Initial Estimation Errors

To determine if initialization creates larger initial errors compared tooverall algorithm functioning, we contrast eA1c performance for theearliest available HbA1c/eA1c pairs for each subject of the testing dataset (374 pairs) to the previously reported overall errors.

Table 7 shows that performance in the early phases on eA1c computationis very similar to overall performance. It is to be noted that, due tothe progression of the treatment in this study, the first laboratoryHbA1c values across the subjects are significantly larger than thesubsequent HbA1c values—8.49% vs 7.43%, p<0.01—which explains theslightly larger MAD, while MARD stays stable.

TABLE 8 Performance of eA1c estimation at initialisation vs. overallperformance First pairs Overall MARD 7.0 6.8 MAD 0.61 0.51

Sensitivity Analysis Sensitivity to Missing Fasting Measurements

To perform this analysis we randomly dropped a fixed percentage offasting BG measurement from the database. The percentage was increasedfrom 0% to 90%. In addition we did not apply the Data Requirements (seebelow) to explore the limits of the “unprotected” algorithm.

The experiment is repeated 10 times and MARD results are presented inFIG. 7. The eA1c algorithm proves extremely resilient to missing datawith overall MARD rising only to 7% from 6.8% when 90% of fastingmeasurements are eliminated from the data base. Correlation doesdecrease more rapidly—from 0.76 to 0.68—but remains high.

This analysis assesses degradation in eA1c performance if the useraccidentally mixes the tags of a 7 point profiles (e.g. post breakfastis identified as fasting, or post-lunch is confused with pre dinner).

To perform this analysis we randomly identify a fixed percentage ofprofiles to be scrambled, then for each selected profile we randomlyidentify 3 pairs of BG measurement (6 values out of the 7 available) andfor each pair we transpose the measurements in the profiles. Thepercentage of scrambled profiles was increased from 0% to 100%.

The experiment is repeated 10 times and MARD results are presented inFIG. 8. Again the eA1c algorithm (and related method, system andcomputer readable medium) is robust to profile scrambling: MARD risesfrom 6.81 to 7.14% when all profiles are scrambled, and correlation goesfrom 0.76 to 0.74. This robustness is attributed to the use of factors(principal components) to quantify the profiles, as discussed above.

Alternate site testing is simulated by adding random noise to each SMBGmeasurements in the testing data set. The simulated error is normallydistributed with zero mean SD=10% (meaning that 95% of the simulated‘AST’ measurements are within 20% of the original SMBG value). Werepeated the simulation 10 times and for each computed MARD, MAD andcorrelation between eA1c and lab HbA1c. Results are presented in Table9. Some of the 10 simulations resulted in marginally degradedperformance (far right column in Table 9), but overall the performanceusing AST was virtually identical to regular SMBG. Again this robustnesscan be attributed to the use of factors (instead of raw SMBG readings)and to the use of average fasting over 5 days in the tracking formula,which diminished the influence of SMBG errors approximately 2.24-fold(square root of 5).

TABLE 9 Performance of HbA1c estimation using simulated AST glucosemeasurements Mean performance Worst performance Original across all ASTacross all AST analysis simulations simulations MARD 6.81 6.84 6.93 MAD0.51 0.51 0.51 Correlation 0.76 0.755 0.750

Data Requirements

The estimation algorithm (and related method, system and computerreadable medium) is built to be robust to missing profiles andoccasional missing fasting values. The following minimum requirementsand conditions determine when reliable HbA1c estimate can be displayedto the user:

-   no fasting values for less than 32 days    -   A1c estimate cannot be computed or displayed. Estimate will be        reinitialized upon fasting BG condition being met again    -   user should be advised to measure fasting glucose-   number of fasting glucose in last 2 weeks is less than 7 or no    fasting glucose in the last 5 days    -   Estimate is computed but possibly estimate value should not be        displayed    -   user should be advised to measure fasting glucose-   time since last profile equal to or is more than 32 days but less    than 64 days    -   Estimate is computed but possibly estimate value should not be        displayed    -   user should be advised to provide profiles-   time since last profile is equal to or more than 64 days or no    profile at all    -   A1c estimate cannot be computed and displayed. Estimate will be        reinitialized upon profile BG condition being met again    -   User should be advised to provide profiles-   time since last profile is less than 32 days, number of fasting    glucose in last 2 weeks is greater or equal to 7, and at least one    fasting BG in last 5 days    -   A1c estimate can be computed and displayed    -   user should be encouraged to measure fasting BG daily

Summarization and Implementation Examples

In diabetes, the struggle for tight glycemic control results in largeblood glucose fluctuations over time. This process is influenced by manyexternal factors, including the timing and amount of insulin injected,food eaten, physical activity, etc. In other words, BG fluctuations arethe measurable result of the action of a complex dynamical system,influenced by many internal and external factors. The macro(human)-level optimization of this system depends on self-treatmentbehavior. Thus, such an optimization has to be based on feedbackutilizing readily available data, such as SMBG.

Although HbA1c is confirmed as the gold standard marker for averageglycemia in both type 1 and type 2 diabetes,^(2,3) HbA1c assaystypically require a laboratory and are routinely done only every fewmonths. On the other hand, we have shown that providing real-timeestimates of HbA1c increases patient motivation and results in improveddiabetes control.²⁹ Thus, tracking of changes in average glycemia isneeded that is independent from laboratory HbA1c assays. SMBG offersthis possibility, provided that appropriate algorithms (e.g., method,system, and computer readable medium) are employed to retrieve SMBGdata.

An aspect of an embodiment of the present invention provides a method,system and computer readable medium for tracking changes in averageglycemia in diabetes, based on a conceptually new approach (method andtechnique) to the retrieval of SMBG data. A principal premise of thisapproach is, among other things, the understanding of HbA1c fluctuationas the measurable effect of the action of an underlying dynamicalsystem. SMBG provides occasional glimpses at the state of this systemand, using these measurements, the hidden underlying system trajectorycan be reconstructed for each individual.

Using compartmental modeling—a technique well established in diabetesresearch³⁵—we have constructed a new two-step algorithm (and relatedmethod, system and computer readable medium) that includes: (i)real-time estimate of HbA1c from fasting glucose readings, updated withany new incoming fasting SMBG data point, and (ii) initialization andcalibration of the estimated HbA1c trace with daily SMBG profiles takenapproximately every month. The estimation of these 7-point profilesincludes another innovative step—a factorial model capturing daily BGvariability into two latent factors.

The development of our method and system followed a robust approachusing a training data set to estimate all model parameters. After theinitial estimation, all parameters were fixed and the algorithm was runprospectively on an independent test data set. As evident from Tables 1and 2 above, the results held, which confirms the robustness of theproposed procedure.

Further, we introduce and use HbA1c Error-Grid analysis inspired by thenow classic Clarke³⁰ or Parkes³¹ Error-Grids, which permits thegraphical representation of accuracy results and the classification ofaccuracy into A- and B-zones signifying “Accurate” readings or “Benign”errors. This analysis resulted in 98.6% readings in the A+B zones—aresult comparable to the accuracy of contemporary SMBG devices³⁴ (seealso FIG. 4).

At every step, we have compared the accuracy of our HbA1c estimator to awell-established linear formula (Nathan et al⁷), showing that ourresults are superior according to all analyses. Most striking is theaccuracy comparison presented by the HbA1c Error-Grid (FIG. 5), whichshows 20% poorer performance by Nathan's formula in the A+B zones. Thereason for this difference is in the nature of the data—it is evidentthat with sparse SMBG readings that include fasting glucose andoccasional 7-point profiles, the mean does not represent well the trueunderlying average of blood glucose fluctuations. As a result, linearformulas based on mean SMBG tend to be significantly biased.

We can therefore conclude that a conceptually new, clinically viable,procedure has been developed for real-time estimation of HBA1c fromself-monitoring data. As seen from the algorithm requirements, theprocedure is readily applicable into devices, systems and networks withlimited processing power, such as for example, but not limited thereto,home SMBG meters.

Example systems for implementation of the present invention will now bedescribed with reference to FIGS. 9-12. FIG. 9 is a high levelfunctional block diagram of an embodiment of the present invention, oran aspect of an embodiment of the present invention.

As shown in FIG. 9, a processor or controller 102 communicates with theglucose monitor or device 101, and optionally the insulin device 100.The glucose monitor or device 101 communicates with the subject 103 tomonitor glucose levels of the subject 103. The processor or controller102 is configured to perform the required calculations. Optionally, theinsulin device 100 communicates with the subject 103 to deliver insulinto the subject 103. The processor or controller 102 is configured toperform the required calculations. The glucose monitor 101 and theinsulin device 100 may be implemented as a separate device or as asingle device. The processor 102 can be implemented locally in theglucose monitor 101, the insulin device 100, or a standalone device (orin any combination of two or more of the glucose monitor, insulindevice, or a stand along device). The processor 102 or a portion of thesystem can be located remotely such that the device is operated as atelemedicine device.

Referring to FIG. 10A, in its most basic configuration, computing device144 typically includes at least one processing unit 150 and memory 146.Depending on the exact configuration and type of computing device,memory 146 can be volatile (such as RAM), non-volatile (such as ROM,flash memory, etc.) or some combination of the two.

Additionally, device 144 may also have other features and/orfunctionality. For example, the device could also include additionalremovable and/or non-removable storage including, but not limited to,magnetic or optical disks or tape, as well as writable electricalstorage media. Such additional storage is the figure by removablestorage 152 and non-removable storage 148. Computer storage mediaincludes volatile and nonvolatile, removable and non-removable mediaimplemented in any method or technology for storage of information suchas computer readable instructions, data structures, program modules orother data. The memory, the removable storage and the non-removablestorage are all examples of computer storage media. Computer storagemedia includes, but is not limited to, RAM, ROM, EEPROM, flash memory orother memory technology CDROM, digital versatile disks (DVD) or otheroptical storage, magnetic cassettes, magnetic tape, magnetic diskstorage or other magnetic storage devices, or any other medium which canbe used to store the desired information and which can accessed by thedevice. Any such computer storage media may be part of, or used inconjunction with, the device.

The device may also contain one or more communications connections 154that allow the device to communicate with other devices (e.g. othercomputing devices). The communications connections carry information ina communication media. Communication media typically embodies computerreadable instructions, data structures, program modules or other data ina modulated data signal such as a carrier wave or other transportmechanism and includes any information delivery media. The term“modulated data signal” means a signal that has one or more of itscharacteristics set or changed in such a manner as to encode, execute,or process information in the signal. By way of example, and notlimitation, communication medium includes wired media such as a wirednetwork or direct-wired connection, and wireless media such as radio,RF, infrared and other wireless media. As discussed above, the termcomputer readable media as used herein includes both storage media andcommunication media.

In addition to a stand-alone computing machine, embodiments of theinvention can also be implemented on a network system comprising aplurality of computing devices that are in communication with anetworking means, such as a network with an infrastructure or an ad hocnetwork. The network connection can be wired connections or wirelessconnections. By way of example, FIG. 10B illustrates a network system inwhich embodiments of the invention can be implemented. In this example,the network system comprises computer 156 (e.g. a network server),network connection means 158 (e.g. wired and/or wireless connections),computer terminal 160, and PDA (e.g. a smart-phone) 162 (or otherhandheld or portable device, such as a cell phone, laptop computer,tablet computer, GPS receiver, mp3 player, handheld video player, pocketprojector, etc. or handheld devices (or non portable devices) withcombinations of such features). In an embodiment, it should beappreciated that the module listed as 156 may be glucose monitor device.In an embodiment, it should be appreciated that the module listed as 156may be a glucose monitor device and/or an insulin device. Any of thecomponents shown or discussed with FIG. 10B may be multiple in number.The embodiments of the invention can be implemented in anyone of thedevices of the system. For example, execution of the instructions orother desired processing can be performed on the same computing devicethat is anyone of 156, 160, and 162. Alternatively, an embodiment of theinvention can be performed on different computing devices of the networksystem. For example, certain desired or required processing or executioncan be performed on one of the computing devices of the network (e.g.server 156 and/or glucose monitor device), whereas other processing andexecution of the instruction can be performed at another computingdevice (e.g. terminal 160) of the network system, or vice versa. Infact, certain processing or execution can be performed at one computingdevice (e.g. server 156 and/or glucose monitor device); and the otherprocessing or execution of the instructions can be performed atdifferent computing devices that may or may not be networked. Forexample, the certain processing can be performed at terminal 160, whilethe other processing or instructions are passed to device 162 where theinstructions are executed. This scenario may be of particular valueespecially when the PDA 162 device, for example, accesses to the networkthrough computer terminal 160 (or an access point in an ad hoc network).For another example, software to be protected can be executed, encodedor processed with one or more embodiments of the invention. Theprocessed, encoded or executed software can then be distributed tocustomers. The distribution can be in a form of storage media (e.g.disk) or electronic copy.

FIG. 11 is a block diagram that illustrates a system 130 including acomputer system 140 and the associated Internet 11 connection upon whichan embodiment may be implemented. Such configuration is typically usedfor computers (hosts) connected to the Internet 11 and executing aserver or a client (or a combination) software. A source computer suchas laptop, an ultimate destination computer and relay servers, forexample, as well as any computer or processor described herein, may usethe computer system configuration and the Internet connection shown inFIG. 11. The system 140 may be used as a portable electronic device suchas a notebook/laptop computer, a media player (e.g., MP3 based or videoplayer), a cellular phone, a Personal Digital Assistant (PDA), a glucosemonitor device, an insulin delivery device, an image processing device(e.g., a digital camera or video recorder), and/or any other handheldcomputing devices, or a combination of any of these devices. Note thatwhile FIG. 11 illustrates various components of a computer system, it isnot intended to represent any particular architecture or manner ofinterconnecting the components; as such details are not germane to thepresent invention. It will also be appreciated that network computers,handheld computers, cell phones and other data processing systems whichhave fewer components or perhaps more components may also be used. Thecomputer system of FIG. 11 may, for example, be an Apple Macintoshcomputer or Power Book, or an IBM compatible PC. Computer system 140includes a bus 137, an interconnect, or other communication mechanismfor communicating information, and a processor 138, commonly in the formof an integrated circuit, coupled with bus 137 for processinginformation and for executing the computer executable instructions.Computer system 140 also includes a main memory 134, such as a RandomAccess Memory (RAM) or other dynamic storage device, coupled to bus 137for storing information and instructions to be executed by processor138.

Main memory 134 also may be used for storing temporary variables orother intermediate information during execution of instructions to beexecuted by processor 138. Computer system 140 further includes a ReadOnly Memory (ROM) 136 (or other non-volatile memory) or other staticstorage device coupled to bus 137 for storing static information andinstructions for processor 138. A storage device 135, such as a magneticdisk or optical disk, a hard disk drive for reading from and writing toa hard disk, a magnetic disk drive for reading from and writing to amagnetic disk, and/or an optical disk drive (such as DVD) for readingfrom and writing to a removable optical disk, is coupled to bus 137 forstoring information and instructions. The hard disk drive, magnetic diskdrive, and optical disk drive may be connected to the system bus by ahard disk drive interface, a magnetic disk drive interface, and anoptical disk drive interface, respectively. The drives and theirassociated computer-readable media provide non-volatile storage ofcomputer readable instructions, data structures, program modules andother data for the general purpose computing devices. Typically computersystem 140 includes an Operating System (OS) stored in a non-volatilestorage for managing the computer resources and provides theapplications and programs with an access to the computer resources andinterfaces. An operating system commonly processes system data and userinput, and responds by allocating and managing tasks and internal systemresources, such as controlling and allocating memory, prioritizingsystem requests, controlling input and output devices, facilitatingnetworking and managing files. Non-limiting examples of operatingsystems are Microsoft Windows, Mac OS X, and Linux.

The term “processor” is meant to include any integrated circuit or otherelectronic device (or collection of devices) capable of performing anoperation on at least one instruction including, without limitation,Reduced Instruction Set Core (RISC) processors, CISC microprocessors,Microcontroller Units (MCUs), CISC-based Central Processing Units(CPUs), and Digital Signal Processors (DSPs). The hardware of suchdevices may be integrated onto a single substrate (e.g., silicon “die”),or distributed among two or more substrates. Furthermore, variousfunctional aspects of the processor may be implemented solely assoftware or firmware associated with the processor.

Computer system 140 may be coupled via bus 137 to a display 131, such asa Cathode Ray Tube (CRT), a Liquid Crystal Display (LCD), a flat screenmonitor, a touch screen monitor or similar means for displaying text andgraphical data to a user. The display may be connected via a videoadapter for supporting the display. The display allows a user to view,enter, and/or edit information that is relevant to the operation of thesystem. An input device 132, including alphanumeric and other keys, iscoupled to bus 137 for communicating information and command selectionsto processor 138. Another type of user input device is cursor control133, such as a mouse, a trackball, or cursor direction keys forcommunicating direction information and command selections to processor138 and for controlling cursor movement on display 131. This inputdevice typically has two degrees of freedom in two axes, a first axis(e.g., x) and a second axis (e.g., y), that allows the device to specifypositions in a plane.

The computer system 140 may be used for implementing the methods andtechniques described herein. According to one embodiment, those methodsand techniques are performed by computer system 140 in response toprocessor 138 executing one or more sequences of one or moreinstructions contained in main memory 134. Such instructions may be readinto main memory 134 from another computer-readable medium, such asstorage device 135. Execution of the sequences of instructions containedin main memory 134 causes processor 138 to perform the process stepsdescribed herein. In alternative embodiments, hard-wired circuitry maybe used in place of or in combination with software instructions toimplement the arrangement. Thus, embodiments of the invention are notlimited to any specific combination of hardware circuitry and software.

The terms “computer-readable medium,” “machine-readable medium,” orother analogous term as used herein is an extensible term that refers toany medium or any memory, that participates in providing instructions toa processor, (such as processor 138) for execution, or any mechanism forstoring or transmitting information in a form readable by a machine(e.g., a computer). Such a medium may store computer-executableinstructions to be executed by a processing element and/or controllogic, and data which is manipulated by a processing element and/orcontrol logic, and may take many forms, including but not limited to,non-volatile medium, volatile medium, and transmission medium.Transmission media includes coaxial cables, copper wire and fiberoptics, including the wires that comprise bus 137. Transmission mediacan also take the form of acoustic or light waves, such as thosegenerated during radio-wave and infrared data communications, or otherform of propagated signals (e.g., carrier waves, infrared signals,digital signals, etc.). Common forms of computer-readable media include,for example, a floppy disk, a flexible disk, hard disk, magnetic tape,or any other magnetic medium, a CD-ROM, any other optical medium,punch-cards, paper-tape, any other physical medium with patterns ofholes, a RAM, a PROM, and EPROM, a FLASH-EPROM, any other memory chip orcartridge, a carrier wave as described hereinafter, or any other mediumfrom which a computer can read.

Various forms of computer-readable media may be involved in carrying oneor more sequences of one or more instructions to processor 138 forexecution. For example, the instructions may initially be carried on amagnetic disk of a remote computer. The remote computer can load theinstructions into its dynamic memory and send the instructions over atelephone line using a modem. A modem local to computer system 140 canreceive the data on the telephone line and use an infra-red transmitterto convert the data to an infra-red signal. An infra-red detector canreceive the data carried in the infra-red signal and appropriatecircuitry can place the data on bus 137. Bus 137 carries the data tomain memory 134, from which processor 138 retrieves and executes theinstructions. The instructions received by main memory 134 mayoptionally be stored on storage device 135 either before or afterexecution by processor 138.

Computer system 140 also includes a communication interface 141 coupledto bus 137. Communication interface 141 provides a two-way datacommunication coupling to a network link 139 that is connected to alocal network 111. For example, communication interface 141 may be anIntegrated Services Digital Network (ISDN) card or a modem to provide adata communication connection to a corresponding type of telephone line.As another non-limiting example, communication interface 141 may be alocal area network (LAN) card to provide a data communication connectionto a compatible LAN. For example, Ethernet based connection based onIEEE802.3 standard may be used such as 10/100BaseT, 1000BaseT (gigabitEthernet), 10 gigabit Ethernet (10 GE or 10 GbE or 10 GigE per IEEE Std802.3ae-2002 as standard), 40 Gigabit Ethernet (40 GbE), or 100 GigabitEthernet (100 GbE as per Ethernet standard IEEE P802.3ba), as describedin Cisco Systems, Inc. Publication number 1-587005-001-3 (6/99),“Internetworking Technologies Handbook”, Chapter 7: “EthernetTechnologies”, pages 7-1 to 7-38, which is incorporated in its entiretyfor all purposes as if fully set forth herein. In such a case, thecommunication interface 141 typically include a LAN transceiver or amodem, such as Standard Microsystems Corporation (SMSC) LAN91C111 10/100Ethernet transceiver described in the Standard Microsystems Corporation(SMSC) data-sheet “LAN91C111 10/100 Non-PCI Ethernet Single ChipMAC+PHY” Data-Sheet, Rev. 15 (02-20-04), which is incorporated in itsentirety for all purposes as if fully set forth herein.

Wireless links may also be implemented. In any such implementation,communication interface 141 sends and receives electrical,electromagnetic or optical signals that carry digital data streamsrepresenting various types of information. Network link 139 typicallyprovides data communication through one or more networks to other datadevices. For example, network link 139 may provide a connection throughlocal network 111 to a host computer or to data equipment operated by anInternet Service Provider (ISP) 142. ISP 142 in turn provides datacommunication services through the world wide packet data communicationnetwork

Internet 11. Local network 111 and Internet 11 both use electrical,electromagnetic or optical signals that carry digital data streams. Thesignals through the various networks and the signals on the network link139 and through the communication interface 141, which carry the digitaldata to and from computer system 140, are exemplary forms of carrierwaves transporting the information.

A received code may be executed by processor 138 as it is received,and/or stored in storage device 135, or other non-volatile storage forlater execution. In this manner, computer system 140 may obtainapplication code in the form of a carrier wave.

The concept of real-time estimation of HbA1c from self-monitoring datahas been developed. As seen from the algorithm and methodologyrequirements discussed herein, the procedure is readily applicable intodevices with limited processing power, such as hoe SMBG meters, and maybe implemented and utilized with the related processors, networks,computer systems, internet, and components and functions according tothe schemes disclosed herein.

FIG. 12 illustrates a system in which one or more embodiments of theinvention can be implemented using a network, or portions of a networkor computers. Although the present invention glucose device may bepracticed without a network.

FIG. 12 diagrammatically illustrates an exemplary system in whichexamples of the invention can be implemented. In an embodiment theglucose monitor may be implemented by the subject (or patient) locallyat home or other desired location. However, in an alternative embodimentit may be implemented in a clinic setting or assistance setting. Forinstance, referring to FIG. 12, a clinic setup 158 provides a place fordoctors (e.g. 164) or clinician/assistant to diagnose patients (e.g.159) with diseases related with glucose and related diseases andconditions. A glucose monitoring device 10 can be used to monitor and/ortest the glucose levels of the patient—as a standalone device. It shouldbe appreciated that while only glucose monitor device 10 is shown in thefigure, the system of the invention and any component thereof may beused in the manner depicted by FIG. 12. The system or component may beaffixed to the patient or in communication with the patient as desiredor required. For example the system or combination of componentsthereof—including a glucose monitor device 10 (or other related devicesor systems such as a controller, and/or an insulin pump, or any otherdesired or required devices or components)—may be in contact,communication or affixed to the patient through tape or tubing (or othermedical instruments or components) or may be in communication throughwired or wireless connections. Such monitor and/or test can be shortterm (e.g. clinical visit) or long term (e.g. clinical stay or family).The glucose monitoring device outputs can be used by the doctor(clinician or assistant) for appropriate actions, such as insulininjection or food feeding for the patient, or other appropriate actionsor modeling. Alternatively, the glucose monitoring device output can bedelivered to computer terminal 168 for instant or future analyses. Thedelivery can be through cable or wireless or any other suitable medium.The glucose monitoring device output from the patient can also bedelivered to a portable device, such as PDA 166. The glucose monitoringdevice outputs with improved accuracy can be delivered to a glucosemonitoring center 172 for processing and/or analyzing. Such delivery canbe accomplished in many ways, such as network connection 170, which canbe wired or wireless.

In addition to the glucose monitoring device outputs, errors, parametersfor accuracy improvements, and any accuracy related information can bedelivered, such as to computer 168, and/or glucose monitoring center 172for performing error analyses. This can provide a centralized accuracymonitoring, modeling and/or accuracy enhancement for glucose centers,due to the importance of the glucose sensors.

Examples of the invention can also be implemented in a standalonecomputing device associated with the target glucose monitoring device.An exemplary computing device (or portions thereof) in which examples ofthe invention can be implemented is schematically illustrated in FIG.10A.

REFERENCES

The following patents, applications and publications as listed below andthroughout this document are hereby incorporated by reference in theirentirety herein, and which are not admitted to be prior art with respectto the present invention by inclusion in this section.

-   -   1. Rahbar S, Blumenfeld O, Ranney H M. Studies of an unusual        hemoglobin in patients with diabetes mellitus. Biochem Biophys        Res Commun. 1969; 36: 838-43.    -   2. The Diabetes Control and Complications Trial Research Group.        The effect of intensive treatment of diabetes on the development        and progression of long-term complications in insulin-dependent        diabetes mellitus. N Engl J Med. 1993; 329: 977-86.    -   3. UK Prospective Diabetes Study (UKPDS) Group. Intensive        blood-glucose control with sulphonylureas or insulin compared        with conventional treatment and risk of complications in        patients with type 2. diabetes (UKPDS 33). The Lancet. 1998;        352: 837-53.    -   4. Manley, Susan. Haemoglobin A1c—A marker for complications of        type 2 diabetes: The experience from the UK Prospective Diabetes        Study (UKPDS), Clinical Chemistry and Laboratory Medicine 2003        41:9 (1182-1190).    -   5. Rohlfing C L, Wiedmeyer H, Little R R, England JD American        Diabetes Association: Diagnosis and Classification of Diabetes        Mellitus. Diabetes Care 2010; 33(Suppl. 1): S62-S69.    -   6. ADA Standards of Care 2011; Diabetes Care, Volume 34,        Supplement 1, January 2011, S11-S61.    -   7. Nathan, D M., Kuenen, J, Borg, R, Zheng, H, Schoenfeld, D,        Heine, R J., For The A1c-Derived Average Glucose (ADAG) Study        Group. Translating the A1C Assay Into Estimated Average Glucose        Values Diabetes Care 31:1473-1478, 2008.    -   8. Makris, Konstantinos; Spanou, L.; Rambaouni-Antoneli, A.;        Koniari, Katerina; Drakopoulos, Ioannis; Rizos, Demetrios A.;        Haliassos, Alexander. Relationship between mean blood glucose        and glycated hemoglobin in Type 2 diabetic patients Diabetic        Medicine 2008 25:2 (174-178).    -   9. Temsch, Wilhelm; Luger, Anton F.; Riedl, Michaela. HbA1c        values calculated from blood glucose levels using truncated        Fourier series and implementation in standard SQL database        language. Methods of Information in Medicine 2008 47:4        (346-355).    -   10. Polneau, S. V.; Lasserre, V.; Fonfrède, M.; Delattre, J.;        Bénazeth, S. A different approach to analyzing age-related HbA1c        values in non-diabetic subjects. Clinical Chemistry and        Laboratory Medicine 2004 42:4 (423-428).    -   11. Nowicka, Paulina; Santoro, Nicola; Liu, Haibei; Lartaud,        Derek; Shaw, Melissa M.; Goldberg, Rachel; Guandalini, Cindy;        Savoye, Mary; Rose, Paulina; Caprio, Sonia. Utility of        hemoglobin A1c for diagnosing prediabetes and diabetes in obese        Children and adolescents. Diabetes Care 2011 34:6 (1306-1311).    -   12. Hamrén, Bengt; Björk, E.; Sunzel, M.; Karlsson, Mats O.        Models for plasma glucose, HbA1c, and hemoglobin        interrelationships in patients with type 2 diabetes following        tesaglitazar treatment. Clinical Pharmacology and Therapeutics        2008 84:2 (228-235).    -   13. Heisler, Michele M.; Piette, John D.; Spencer, Michael S.;        Kieffer, Edie; Vijan, Sandeep. The relationship between        knowledge of recent HbA1c values and diabetes care understanding        and self-management. Diabetes Care 2005 28:4 (816-822).    -   14. Landgraf, Rüdiger. The relationship of postprandial glucose        to HbA1c. Diabetes Metab Res Rev 2004 20:SUPPL 2 (S9-S12).    -   15. Yamamoto-Honda, Ritsuko; Kitazato, Hiroji; Hashimoto,        Shinij; Takahashi, Yoshihiko; Yoshida, Yoko; Hasegawa, Chiyoko;        Akanuma, Yasuo; Noda, Mitsuhiko Distribution of blood glucose        and the correlation between blood glucose and hemoglobin Alc        levels in diabetic outpatients. Endocrine Journal 2008 55:5        (913-923).    -   16. Goldstein D E, Little R R, Lorenz R A et al. Tests of        glycemia in diabetes. Diabetes Care. 2004; 27: 1761-73.    -   17. Trevino, G. On A1c and its dependence on PG level. Diabetes        Research and Clinical Practice 2006 73:1 (111-112).    -   18. Trevino, G. On the weighted-average relationship between        plasma glucose and HbA1c. Diabetes Care 2006 18:2 (466-467).    -   19. Trevino, G. A nonlinear relation between glucose and A1c.        Diabetes Research and Clinical Practice 2008 79:3 (e14).    -   20. Zielke, Roland; Henrichs, H. R. Use of the HbA1c        determination as long-term parameter in diabetes control.        Klinisches Labor 1993 39:12 (988-990).    -   21. Ollerton, R. L.; Luzio, S. D.; Owens, D. R. Contribution of        fasting and postprandial plasma glucose to HbA(1c) Diabetic        Medicine 2005 22:7 (954-955.    -   22. Osterman-Golkar, S. M.; Vesper, H. W. Assessment of the        relationship between glucose and A1c using kinetic modelling.        Journal of Diabetes and its Complications 2006 20:5 (285-294).    -   23. Kahrom, M. An innovative mathematical model: A key to the        riddle of HbA1c. International Journal of Endocrinology 2010        Article Number 481326.    -   24. Kovatchev, B. P.; Cox, D. J.; Straume, M.; Farhy, L. S.        Association of self-monitoring blood glucose profiles with        glycolysated hemoglobin in patients with insulin-dependent        diabetes. Methods in Enzymology 2000 321 (410-417)    -   25. Kovatchev B P, Straume M, Cox D J, Farhy L S. Risk analysis        of blood glucose data: A quantitative approach to optimizing the        control of insulin dependent diabetes. J of Theoretical        Medicine, 3:1-10, 2001.    -   26. Kovatchev B P, Cox D J. Numerical Estimation of HbA_(1c)        from Routine Self-Monitoring Data in People With Type 1 and Type        2 Diabetes Mellitus (2004). In: Methods in Enzymology, 384:        Numerical Computer Methods, Part E: 94-106. M Johnson and L        Brand, Eds., Academic Press, NY. ISBN: 978-0-12-182789-2.    -   27. Kovatchev B P, Cox D J, Kumar A, Gonder-Frederick L A,        Clarke W L (2003). Algorithmic Evaluation of Metabolic Control        and Risk of Severe Hypoglycemia in Type 1 and Type 2 Diabetes        Using Self-Monitoring Blood Glucose (SMBG) Data. Diabetes        Technology and Therapeutics, 5 (5): 817-828.    -   28. Kovatchev B P, Otto E, Cox D, Gonder-Frederick L, Clarke W.        Evaluation of a new measure of blood glucose variability in        diabetes. Diabetes Care. 2006 November; 29 (11): 2433-8.    -   29. Kovatchev B P, Mendosa P, Anderson S, Hawley J S, Ritterband        L M, Gonder-Frederick L. Effect of automated bio-behavioral        feedback on the control of type 1 diabetes. Diabetes Care. 2011        February; 34 (2):302-7. Epub 2011 Jan 7.    -   30. Clarke W L, Cox D, Gonder-Frederick L A, Carter W, Pohl.        S L. Evaluating clinical accuracy of systems for self-monitoring        of blood glucose. Diabetes Care. 1987;10(5):622-8.    -   31. Parkes J L, Slatin S L, Pardo S, Ginsberg B H. A new        consensus error grid to evaluate the clinical significance of        inaccuracies in the measurement of blood glucose. Diabetes Care.        2000;23(8):1143-8.    -   32. Kovatchev B P, Gonder-Frederick L A, Cox D J, Clarke W L.        Evaluating the accuracy of continuous glucose-monitoring        sensors: continuous glucose-error grid analysis illustrated by        TheraSense Freestyle Navigator data. Diabetes Care.        2004;27:1922-8.    -   33. Clinical and Laboratory Standards Institute (CLSI).        Performance Metrics for Continuous Interstitial Glucose        Monitoring: Approved Guideline. CLSI document, POCT-A, 2008.    -   34. Boren S A, Clarke W L. Analytical and clinical performance        of blood glucose monitors. J Diabetes Sci Technol.        2010;4(1):84-97.    -   35. Cobelli C, Dalla Man C, Sparacino G, Magni L, Nicolao G, and        Kovatchev B P (2009). Diabetes: Models, Signals, and Control.        IEEE Reviews in Biomedical Engineering, 2: 54-96.

The devices, systems, computer readable medium, algorithms, models, andmethods of various embodiments of the invention disclosed herein mayutilize aspects disclosed in the following references, applications,publications and patents and which are hereby incorporated by referenceherein in their entirety (and which are not admitted to be prior artwith respect to the present invention by inclusion in this section):

-   -   A. U.S. patent application Ser. No. 13/637,359, entitled        “Method, System, and Computer Program Product for Improving the        Accuracy of Glucose Sensors Using Insulin Delivery Observation        in Diabetes”, filed Sep. 25, 2012;    -   B. U.S. patent application Ser. No. 13/634,040, entitled “Method        and System for the Safety, Analysis, and Supervision of Insulin        Pump Action and Other Modes of Insulin Delivery in Diabetes”,        filed Sep. 11, 2012.    -   C. International Patent Application Serial No.        PCT/US2012/052422, entitled “Method, System and Computer        Readable Medium for Adaptive Advisory Control of Diabetes”,        filed Aug. 26, 2012;    -   D. International Patent Application Serial No.        PCT/US2012/043910, entitled “Unified Platform For Monitoring and        Control of Blood Glucose Levels in Diabetic Patients” filed Jun.        23, 2012;    -   E. International Patent Application Serial No.        PCT/US2012/043883, entitled “Methods and Apparatus for Modular        Power Management and Protection of Critical Services in        Ambulatory Medical Devices”, filed Jun. 22, 2012;    -   F. U.S. patent application Ser. No. 13/394,091, entitled        “Tracking the Probability for Imminent Hypoglycemia in Diabetes        from Self-Monitoring Blood Glucose (SMBG) Data filed Mar. 2, 12;    -   G. U.S. patent application Ser. No. 13/393,647 filed Mar. 1, 12,        National Stage of PCT/US2010/047386, entitled “System, Method        and Computer Program Product for Adjustment of Insulin Delivery        (AID) in Diabetes Using Nominal Open-Loop Profiles” filed Aug.        31, 2010;    -   H. U.S. patent application Ser. No. 13/380,839 filed Feb. 10,        2012, National Stage of PCT/US2010/040097, entitled “System,        Method and Computer Stimulation Environment for In Silico Trials        in Prediabetes and Type 2 Diabetes” filed Jun. 25, 2010;    -   I. International Patent Application Serial No.        PCT/US2011/029793, entitled “Method, System and Computer Program        Product for Improving the Accuracy of Continuous Glucose Sensors        Using Insulin Delivery Observation in Diabetes” filed Mar. 24,        2011;    -   J. International Patent Application Serial No.        PCT/US2011/028163, entitled “Method and System for the Safety,        Analysis, and Supervision of Insulin Pump Action and Other Modes        of Insulin Delivery in Diabetes” filed Mar. 11, 2011;    -   K. U.S. patent application Ser. No. 12/975,580, entitled        “System, Method and Computer Program Product for Adjustment of        Insulin Delivery (AID) in Diabetes Using Nominal Open-Loop        Profiles”, filed Dec. 22, 2010;    -   L. International Patent Application Serial No.        PCT/US2010/047711, entitled “Tracking the Probability for        Hypoglycemia in Diabetes from Self-Monitoring Blood Glucose        (SMBG) Data, filed Sep. 2, 2010;    -   M. International Patent Application Serial No.        PCT/US2010/047386, entitled “System Coordinator and Modular        Architecture for Open-Loop and Closed-Loop Control of Diabetes”,        Aug. 31, 2010;    -   N. International Patent Application Serial No.        PCT/US2010/036629, entitled “System Coordinator and Modular        Architecture for Open-Loop and Closed-Loop Control of Diabetes”,        filed May 28, 2010;    -   O. International Patent Application Serial No.        PCT/US2010/025405, entitled “Method, System and Computer Program        Product for CGM-Based Prevention of Hypoglycemia via        Hypoglycemia Risk Assessment and Smooth Reduction Insulin        Delivery,” filed Feb. 25, 2010;    -   P. International Patent Application Serial No.        PCT/US2009/065725, entitled “Method, System, and Computer        Program Product for Tracking of Blood Glucose Variability in        Diabetes from Data,” filed Nov, 24, 2009;    -   Q. International Patent Application Serial No.        PCT/US2008/082063, entitled “Model Predictive Control Based        Method for Closed-Loop Control of Insulin Delivery in Diabetes        Using Continuous Glucose Sensing”, filed Oct. 31, 2008;    -   R. PCT/US2008/069416, entitled “Method, System and Computer        Program Product for Evaluation of Insulin Sensitivity,        Insulin/Carbohydrate Ratio, and Insulin Correction Factors in        Diabetes from Self-Monitoring Data”, filed Jul. 8, 2008;    -   S. PCT/US2008/067725, entitled “Method, System and Computer        Simulation Environment for Testing of Monitoring and Control        Strategies in Diabetes,” filed Jun. 20, 2008;    -   T. PCT/US2008/067723, entitled “LQG Artificial Pancreas Control        System and Related Method”, filed on Jun. 20, 2008;    -   U. U.S. patent application Ser. No. 12/516,044, entitled        “Method, System, and Computer Program Product for the Detection        of Physical Activity by Changes in Heart Rate, Assessment of        Fast Changing Metabolic States, and Applications of Closed and        Open Control Loop in Diabetes”, filed May 22, 2009;    -   V. PCT/US2007/085588, entitled “Method, System, and Computer        Program Product for the Detection of Physical Activity by        Changes in Heart Rate, Assessment of Fast Changing Metabolic        States, and Applications of Closed and Open Control Loop in        Diabetes”, filed Nov. 27, 2007;    -   W. U.S. Ser. No. 11/943,226, entitled “Systems, Methods and        Computer Program Codes for Recognition of Patterns of        Hyperglycemia and Hypoglycemia, Increased Glucose Variability,        and Ineffective Self-Monitoring in Diabetes” filed Nov. 20,        2007;    -   X. U.S. patent application Ser. No. 11/578,831, entitled        “Method, System and Computer Program Product for Evaluating the        Accuracy of Blood Glucose Monitoring Sensors/Devices”, filed        Oct. 18, 2006;    -   Y. PCT International Application Serial No. PCT/US2005/013792,        entitled “Method, System, and Computer Program Product for        Evaluation of the Accuracy of Blood Glucose Monitoring        Sensors/Devices”, filed Apr. 21, 2005;    -   Z. PCT International Application Serial No. PCT/US01/09884,        entitled “Method, System, and Computer Program Product for        Evaluation of Glycemic Control in Diabetes Self-Monitoring        Data”, filed Mar. 29, 2001;    -   AA. U.S. Pat. No. 7,025,425 B2 issued Apr. 11, 2006, entitled        “Method, System, and Computer Program Product for the Evaluation        of Glycemic Control in Diabetes from Self-Monitoring Data”;    -   BB. U.S. patent application Ser. No. 11/305,946 filed Dec. 19,        2005 entitled “Method, System, and Computer Program Product for        the Evaluation of Glycemic Control in Diabetes from        Self-Monitoring Data” (Publication No. 2006/0094947);    -   CC. PCT International Application Serial No. PCT/US2003/025053,        filed Aug. 8, 2003, entitled “Method, System, and Computer        Program Product for the Processing of Self-Monitoring Blood        Glucose (SMBG) Data to Enhance Diabetic Self-Management;”    -   DD. U.S. patent application Ser. No. 10/524,094 filed Feb. 9,        2005 entitled “Managing and Processing Self-Monitoring Blood        Glucose” (Publication No. 2005/214892);    -   EE. U.S. Ser. No. 12/065,257, filed Aug. 29, 2008, entitled        “Accuracy of Continuous Glucose Sensors;”    -   FF. PCT International Application Serial No PCT/US2006/033724,        filed Aug. 29, 2006, entitled “Method for Improvising Accuracy        of Continuous Glucose Sensors and a Continuous Glucose Sensor        Using the Same”;    -   GG. U.S. Ser. No. 12/159,891, filed Jul. 2, 2008, entitled        “Method, System and Computer Program Product for Evaluation of        Blood Glucose Variability in Diabetes from Self-Monitoring        Data”;    -   HH. PCT International Application No. PCT/US2007/000370, filed        Jan. 5, 2007, entitled “Method, System and Computer Program        Product for Evaluation of Blood Glucose Variability in Diabetes        from Self-Monitoring Data”;    -   II. U.S. patent application Ser. No. 11/925,689 and PCT        International Patent Application No. PCT/US2007/082744, both        filed Oct. 26, 2007, entitled “For Method, System and Computer        Program Product for Real-Time Detection of Sensitivity Decline        in Analyte Sensors”;    -   JJ. U.S. Ser. No. 10/069,674, filed Feb. 22, 2002, entitled        “Method and Apparatus for Predicting the Risk of Hypoglycemia”;    -   KK. PCT International Application No. PCT/US00/22886, filed Aug.        21, 2000, entitled “Method and Apparatus for Predicting the Risk        of Hypoglycemia”; and    -   LL. U.S. Pat. No. 6,923,763 B1, issued Aug. 2, 2005, entitled        “Method and Apparatus for Predicting the Risk of Hypoglycemia”.

In summary, while the present invention has been described with respectto specific embodiments, many modifications, variations, alterations,substitutions, and equivalents will be apparent to those skilled in theart. The present invention is not to be limited in scope by the specificembodiment described herein. Indeed, various modifications of thepresent invention, in addition to those described herein, will beapparent to those of skill in the art from the foregoing description andaccompanying drawings. Accordingly, the invention is to be considered aslimited only by the spirit and scope of the following disclosure,including all modifications and equivalents.

Still other embodiments will become readily apparent to those skilled inthis art from reading the above-recited detailed description anddrawings of certain exemplary embodiments. It should be understood thatnumerous variations, modifications, and additional embodiments arepossible, and accordingly, all such variations, modifications, andembodiments are to be regarded as being within the spirit and scope ofthis application. For example, regardless of the content of any portion(e.g., title, field, background, summary, abstract, drawing figure,etc.) of this application, unless clearly specified to the contrary,there is no requirement for the inclusion in any claim herein or of anyapplication claiming priority hereto of any particular described orillustrated activity or element, any particular sequence of suchactivities, or any particular interrelationship of such elements.Moreover, any activity can be repeated, any activity can be performed bymultiple entities, and/or any element can be duplicated. Further, anyactivity or element can be excluded, the sequence of activities canvary, and/or the interrelationship of elements can vary.

Unless clearly specified to the contrary, there is no requirement forany particular described or illustrated activity or element, anyparticular sequence or such activities, any particular size, speed,material, dimension or frequency, or any particularly interrelationshipof such elements. Accordingly, the descriptions and drawings are to beregarded as illustrative in nature, and not as restrictive. Moreover,when any number or range is described herein, unless clearly statedotherwise, that number or range is approximate. When any range isdescribed herein, unless clearly stated otherwise, that range includesall values therein and all sub ranges therein. Any information in anymaterial (e.g., a United States/foreign patent, United States/foreignpatent application, book, article, etc.) that has been incorporated byreference herein, is only incorporated by reference to the extent thatno conflict exists between such information and the other statements anddrawings set forth herein. In the event of such conflict, including aconflict that would render invalid any claim herein or seeking priorityhereto, then any such conflicting information in such incorporated byreference material is specifically not incorporated by reference herein.

What is claimed is:
 1. A system for providing a real-time estimate ofglycosylated hemoglobin (HbA1c) of a patient from a self-monitoringblood glucose (SMBG) measurement, and tracking changes in averageglycemia of said patient over time, comprising: one or more processors;and a processor-readable memory having stored thereonprocessor-executable instructions that when executed cause at least oneof said one or more processors to: receive a fasting SMBG measurementfrom said patient, compute a glycation value using said fasting SMBGmeasurement in a predetermined glycation equation, update said glycationvalue by using an updated SMBG value in said predetermined glycationequation, said updated SMBG value being based on a subsequent fastingSMBG measurement from said patient, compute an updated estimate of HbA1cusing an initial estimate of HbA1c and said updated glycation value in apredetermined HbA1c estimation equation, and output said updatedestimate of HbA1c to a user.
 2. A computer-implemented method forproviding a real-time estimate of glycosylated hemoglobin (HbA1c) of apatient from a self-monitoring blood glucose (SMBG) measurement, andtracking changes in average glycemia of said patient over time, saidmethod comprising: receiving, by a processor, a fasting SMBG measurementfrom said patient; computing, by a processor, a glycation value usingsaid fasting SMBG measurement in a predetermined glycation equation;updating, by a processor, said glycation value by using an updated SMBGvalue in said predetermined glycation equation, said updated SMBG valuebeing based on a subsequent fasting SMBG measurement from said patient;computing, by a processor, an updated estimate of HbA1c using an initialestimate of HbA1c and said updated glycation value in a predeterminedHbA1c estimation equation; and outputting, by a processor, said updatedestimate of HbA1c to a user.